Enhanced drug delivery in transdermal systems

ABSTRACT

A composition for transdermal administration resulting from an admixture includes: a therapeutically effective amount of a drug that includes a parent drug and a prodrug; and a pharmaceutically acceptable carrier, wherein the parent drug and prodrug are individually present in an amount sufficient for a pharmacological effect. In a preferred embodiment, the admixture includes: a therapeutically effective amount of a pharmaceutically active agent that includes a corresponding steroid and a steroid derivative; and a carrier for the pharmaceutically active agent. The steroid and the corresponding steroid derivative are present in a weight ratio of 10:1 to 1:10 steroid:corresponding steroid derivative. In a preferred embodiment ratio is 6:1 to 1:6. In a preferred embodiment, the corresponding steroid derivative is a steroid ester. In another preferred embodiment, the carrier is a polymer that includes a pressure-sensitive adhesive. In another preferred embodiment, the parent drug is an ACE inhibitor such as ramipril and the prodrug is an ACE inhibitor prodrug such as ramipril ethyl and/or methyl ester.

This application is a continuation of application Ser. No. 10/330,281filed Dec. 30, 2002, now U.S. Pat. No. 7,456,159 which is a continuationof PCT/US02/16579, filed Jun. 18, 2002, which claims benefit of U.S.application Ser. No. 09/948,107, filed Sep. 7, 2001, and U.S.Provisional Application No. 60/298,381, filed Jun. 18, 2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to transdermal drug delivery systems. Inparticular, the present invention relates to transdermal drug deliverysystems for delivering a therapeutically effective amount of a drug thatincludes a parent drug and a prodrug. The present invention, inparticular, relates to transdermal drug delivery systems for deliveringsteroids, and to methods of making and using the same.

2. Description of the Related Art

The use of a transdermal drug delivery system, for example apressure-sensitive adhesive containing a drug, as a means foradministering therapeutically effective amounts of the medicament iswell known. Such known delivery systems involve incorporation of a druginto a carrier such as a polymeric and/or a pressure-sensitive adhesiveformulation or other forms of carriers. The pressure-sensitive adhesivemust adhere effectively to the skin and permit migration of the drugfrom the carrier through the skin and into the bloodstream of thepatient.

Steroids such as estradiol and norethindrone are especially well knownfor use in transdermal drug delivery systems, in particular, as hormonereplacement therapy. These steroids may be administered singularly, suchas the estradiol transdermal drug delivery system sold under thetrademark Vivelle7 and Vivelle-Dot

manufactured by Noven Pharmaceuticals, Inc. of Miami, Fla. See also U.S.Pat. No. 6,221,383. Alternatively, two or more steroids may beadministered together, such as the estradiol/norethindrone acetatetransdermal drug delivery system sold under the trademark CombiPatch®also manufactured by Noven Pharmaceuticals. See also U.S. Pat. No.6,221,383. See also U.S. Pat. No. 5,474,783.

Transdermal drug delivery systems with more than one drug are generallymore difficult to formulate in view of different interactions with eachdrug and the carrier, excipients, etc., even the other drug present. Inaddition, government agencies that regulate pharmaceutical products,such as the FDA in the United States, require more testing of multipledrugs, individually as well as together to establish efficacy. Thus,when a drug, such as a steroid is administered, it is generallyadministered in one form only (e.g., norethindrone or norethindroneacetate). See, e.g., U.S. Pat. No. 6,149,935.

The use of a steroid as an additive to act as a crystallizationinhibitor in transdermal drug delivery devices where the drug is ahormone is described in WO 99/15156. WO 99/15156 teaches the steroid ispresent in the device in an amount insufficient to provide significantpharmaceutical or physiological effect. Other patents include U.S. Pat.Nos. 5,633,242; 4,906,169; 5,711,962; 6,153,216; 5,898,032; 5,811,117;and 6,024,974.

One problem in the delivery of drugs, such as steroids from transdermaldrug delivery systems lies in the rate of drug release (commonly called“flux” or “permeation rate”) from the transdermal system. Specifically,there are many applications in which it would be desirable to have agreater flux of drug (e.g., steroid) from the system. There are alsomany applications in which it would be desirable to have a decreasedflux of drug (e.g., steroid) from the system. In other words, oneproblem in transdermal drug delivery lies in controlling the transfer ofdrug from the composition, across the skin and into the subject'sbloodstream, thus, controlling the blood profile level of the drug.

One known method for selectively controlling the permeation rate of adrug from a transdermal composition is described in U.S. Pat. No.5,474,783, assigned to the assignee of the present invention. In thispatent, two or more polymers are used in combination to adjust thesolubility of the drug in the carrier system. While this method ofcontrolling permeation rate generally works well, it is not alwaysreadily possible to control the permeation rate of the drug in thedesired manner, such as to achieve a longer or shorter duration of drugdelivery and to increase or delay onset of a therapeutic effect.

Another problem in the delivery of drugs, in particular steroids, is thetendency for drugs (e.g., steroids) to crystallize in the carrier of thetransdermal system. This results in less steroid being available fortransdermal administration. Although the addition of solubilizingagents, such as PVP, help to inhibit crystallization, there are someapplications where it is desirable to have a greater crystal inhibitingeffect.

U.S. Pat. No. 6,368,616 B1 discloses two phase (aqueous and oily) liquidcompositions comprising at least: (A) an NSAID; (B) an alcohol (definedas melt point depressing agent, column 4, line 60); (C) water; andoptionally (D) a second melt point depressing agent. The compositionsare described as having two phases, with substantially melted solids at25° C. The “second melt point depressing agents,” referred to in the'616 patent are defined as solvents, enhancers, adjuvants or drugs, suchas anesthetics or NSAIDs.

U.S. Pat. No. 4,529,601 discloses combination of two different localanesthetic base drugs that melt together at room temperature. Preferredmelting points are below 40° C., more preferably, below 25° C.

SUMMARY OF THE INVENTION

One object of the invention is to overcome the disadvantages of theknown art described above. Another object of the invention is to providea transdermal drug delivery system that has increased control over thepermeation rate of the drug, onset of effect and/or duration of deliveryand/or effect of the drug. Yet another object of the invention is toprovide a transdermal drug delivery system that has an improved flux ofsteroid compared to a system of equal size. Still another object of theinvention is to provide a composition that has reduced, or no, crystalformation in the transdermal drug delivery system.

In accomplishing the foregoing and other objects, there has beenprovided according to one aspect of the present invention a composition,preferably a dermal composition, resulting from an admixture thatincludes: a therapeutically effective amount of a drug that includes aparent drug and a prodrug; and a pharmaceutically acceptable carrier,wherein the parent drug and prodrug are individually present in anamount sufficient for a pharmacological effect. In a preferredembodiment, the composition has an onset of the therapeutic effect thatis longer or shorter than an identical composition having apharmacologically equivalent amount of the parent drug or prodrug alone.In another preferred embodiment, the composition has a blood levelprofile that is different from an identical composition having apharmacologically equivalent amount of the parent drug or prodrug alone.In yet another preferred embodiment, the composition has a permeationrate that is faster or slower than an identical composition having apharmacologically equivalent amount of the parent drug or prodrug alone.In still another preferred embodiment, the composition has a duration ofthe therapeutic effect that is longer or shorter than a compositionhaving a pharmacologically equivalent amount of the parent drug alone.In another preferred embodiment, the prodrug is more lipophilic than theparent drug and the prodrug has a greater permeation rate through theskin. In still another preferred embodiment, the melting point of thecombined parent drug and prodrug is less than the melting point ofeither the parent drug or prodrug alone. According to another preferredembodiment, the carrier comprises a pressure-sensitive adhesive thatincludes two or more polymers, and wherein the permeation of the drug isadjusted by changing the type and/or proportions of the two or morepolymers.

According to a preferred aspect of the invention, there has beenprovided a composition, preferably a dermal composition, resulting froman admixture that includes: a therapeutically effective amount of apharmaceutically active agent that includes a steroid and acorresponding steroid derivative that provides a source oftherapeutically active steroid; and a carrier for the pharmaceuticallyactive agent, wherein the steroid and steroid derivative are present ina weight ratio of 10:1 to 1:10 steroid:steroid derivative. In apreferred embodiment, the steroid derivative is a steroid ester. Inanother preferred embodiment the carrier is a polymer that includes apressure-sensitive adhesive.

According to another aspect of the invention, there has been provided acomposition for the transdermal delivery of a drug resulting from anadmixture that includes: a therapeutically effective amount of a drugthat includes an ACE inhibitor and a corresponding ACE inhibitorprodrug; and a pharmaceutically acceptable carrier. Preferably, the ACEinhibitor is ramipril and the prodrug is ramipril methyl and/or ethylester.

According to another aspect of the invention, there has been provided amethod of making a composition described above that includes forming amixture of the parent drug and prodrug (preferably a steroid andcorresponding steroid derivative) and carrier. Preferably, the carrieris a polymer and the method further includes: forming the blend into apolymer matrix; and drying the polymer matrix to remove volatilesolvents to form the composition.

According to another aspect of the invention, there has been provided amethod of treating a human or an animal with a therapeutically effectiveamount of a pharmaceutically active agent, that includes the steps of:applying to the skin of an animal or human being, the compositiondescribed above; and maintaining the composition in contact with theskin for a predetermined length of time sufficient to administer thetherapeutically amount of the pharmaceutically active agent.

Further objects, features and advantages of the present invention willbecome apparent from the detailed description of preferred embodimentswhich follows.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph illustrating the drug flux from a compositioncontaining norethindrone acetate and estradiol, and a compositioncontaining combined norethindrone/norethindrone acetate and estradiol.

FIG. 2 is a graph illustrating the flux of norethindrone acetate from acomposition containing norethindrone acetate and estradiol, combinednorethindrone/norethindrone acetate from a composition containingnorethindrone/norethindrone acetate and estradiol, and norethindronefrom a composition containing norethindrone and estradiol.

FIG. 3 is a graph illustrating the drug flux of combinedtestosterone/testosterone acetate from a composition containingtestosterone/testosterone acetate, the flux of testosterone acetate fromthe same composition, the flux of testosterone from the same compositionand the flux of testosterone from a transdermal drug delivery systemcalled Testoderm 7 sold by Alza, Inc.

FIG. 4 is a graph illustrating drug and prodrug theoretical permeationfrom a single transdermal composition containing a parent drug and twoprodrugs.

FIG. 5 shows cumulative permeation for norethindrone for variouscombinations of parent drug/prodrug.

FIG. 6 shows cumulative permeation for norethindrone acetate for variouscombinations of parent drug/prodrug.

FIG. 7 shows combined cumulative permeation for norethindrone andnorethindrone acetate for various combinations of parent drug/prodrug.

FIG. 8 shows cumulative permeation for ramipril and its prodrugs.

FIG. 9 shows cumulative permeation for ramipril prodrugs, with andwithout enhancers.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides, inter alia, a transdermal drug deliverycomposition for administration of a therapeutically effective amount ofa drug, by delivery of a combined parent drug and prodrug.

A preferred embodiment of the present invention provides, inter alia, atransdermal drug delivery composition for administration of atherapeutically effective amount of a steroid, particularly transdermalcompositions having a greater flux than known compositions.

As used herein, “transdermal” delivery is intended both transdermal (or“percutaneous” or “dermal”) and transmucosal administration, i.e.,delivery by passage of a drug through the skin or mucosal tissue andinto the bloodstream.

As used herein, the term, “flux” (also called “permeation rate”) isdefined as the absorption of the drug through the skin or mucosa, and isdescribed by Fick's first law of diffusion:J=−D(dCm/dx),where J is the flux in g/cm²/sec, D is the diffusion coefficient of thedrug through the skin or mucosa in cm²/sec and dCm/dx is theconcentration gradient of the drug across the skin or mucosa.

As used herein, a “drug” is defined as any therapeutically,prophylactically and/or pharmacologically or physiologically beneficialactive substance, or mixture thereof, which is delivered to a livingorganism to produce a desired, usually beneficial, effect. Morespecifically, any drug which is capable of producing a pharmacologicalresponse, localized or systemic, irrespective of whether therapeutic,diagnostic, or prophylactic in nature, in plants or animals is withinthe contemplation of the invention. The drug may be phamacologicallyactive or may require further biotransformation. The term “drug”encompasses both “parent drug” and “prodrug” as defined below. The drugshould be used in amounts sufficient to prevent, cure, diagnose or treata disease or other condition, as the case may be.

As used herein, a “parent drug” is defined the same as a “drug,” exceptthat it does not undergo biotransformation to render it morepharmacologically active.

As used herein, a “prodrug” is defined as a pharmacologically lessactive derivative of a parent drug molecule that requiresbiotransformation, either spontaneous or enzymatic, within the organismto release the more active parent drug. Prodrugs are variations orderivatives of the parent drugs which have groups cleavable undermetabolic conditions. Prodrugs become the parent drugs which arepharmaceutically active in vivo, when they undergo solvolysis underphysiological conditions or undergo enzymatic degradation. Prodrugs maybe called single, double, triple, etc., depending on the number ofbiotransformation steps required to release the active parent drugwithin the organism, and indicating the number of functionalitiespresent in a precursor-type form. Prodrugs commonly known in the artinclude acid derivatives well known to practitioners of the art, suchas, for example, esters prepared by reaction of the parent acids with asuitable alcohol, or amides prepared by reaction of the parent acidcompound with an amine, or basic groups reacted to form an acylated basederivative. See, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier,Amsterdam 1985; Silverman, The Organic Chemistry of Drug Design and DrugAction, pp. 352-401, Academic Press, San Diego, Calif., 1992; andBurger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp.172-178, 949-982 (1995).

As used herein, “pharmacologically equivalent amount” is defined as anamount of the parent drug or prodrug that has an equivalent therapeuticeffect as a selected combined amount of the parent drug and prodrug.

As used herein “blood profile level” is defined as the concentration inblood level of the parent drug or prodrug over a selected period oftime, usually from beginning of administration.

As used herein, a steroid is defined as a family of lipid compounds thatincludes the sterols, bile acids, cardiac glycosides, saponins,corticoid steroids and hormones. The basic structure of the steroid is awell known 4 ring fused structure.

According to one aspect of the invention, the inventor has found thatthe permeation rate of the blood profile level of a subject beingadministered a drug transdermally can be more readily controlled by theuse of a prodrug in combination with the parent drug. By administering aparent drug and prodrug combination, the blood profile level can beaffected by two significant aspects: (1) overall solubility of theparent drug/prodrug in the carrier; and (2) selection of the prodrug toaffect its transport through the skin and metabolism into the parentdrug in the body of the subject.

By controlling the overall solubility of the parent drug/prodrug withinthe carrier, the overall saturation concentration of the parentdrug/prodrug, and hence the rate of release of the drug from the carrierwill be increased and/or decreased. The overall solubility of the parentdrug/prodrug in the carrier can be controlled by adjusting theconcentration of the parent drug and prodrug relative to each other.This method relies upon the different solubilities that the parent drugand prodrug will have in the composition, due to the different polarityof the parent drug and prodrug and other factors such as hydrogenbonding. Changes in substituents on the molecule can significantlyeffect the solubility. Also, the use of co-solvents and othersolubilizing agents can be used to adjust the solubilities of the parentdrug and prodrug in the composition.

Another related method for controlling the overall solubility of theparent drug/prodrug concentration is to use a solubility based selectionof the polymers that make up the carrier. A solubility based selectionof polymers to optimize the permeation rate of a parent drug or prodrugwithout its prodrug or parent drug is described in the '783 patentdescribed above, which is incorporated by reference in its entirety. Thesame principles regarding the solubility of a drug in a polymer blendwill also apply to a carrier with a parent drug/prodrug combination.

The term “blend” is used herein to mean that there is no, orsubstantially no, chemical reaction or cross-linking (other than simpleH-bonding) between the polymers in the polymer adhesive carrier.

The polymers comprising the multiple polymer adhesive carrier are inertto the drug, and are preferably immiscible with each other. Forming ablend of multiple polymers results in an adhesive carrier having acharacteristic “net solubility parameter,” the selection of whichadvantageously permits a selectable modulation of the delivery rate ofthe drug by adjusting the solubility of the drug in the multiple polymeradhesive carrier.

Solubility parameter, also referred to herein as “SP”, has been definedas the sum of all the intermolecular attractive forces, which areempirically related to the extent of mutual solubility of many chemicalspecies. A general discussion of solubility parameters is found in anarticle by Vaughan, “Using Solubility Parameters in CosmeticsFormulation,” J. Soc. Cosmet. Chem., Vol. 36, pages 319-333 (1985). Manymethods have been developed for the determination of solubilityparameters, ranging from theoretical calculations to totally empiricalcorrelations. The most convenient method is Hildebrand's method, whichcomputes the solubility parameter from molecular weight, boiling pointand density data, which are commonly available for many materials andwhich yields values which are usually within the range of other methodsof calculation:SP=(ΔEv/V)^(1/2),

where V=molecular weight/density and ΔE_(V)=energy of vaporization.

Alternatively written, SP=(ΔH_(V)/V-RT/V)^(1/2)

where ΔH_(V)=heat of vaporization, R=gas constant, and T is the absolutetemperature, ° K. For materials, such as high molecular weight polymers,which have vapor pressures too low to detect, and thus for which ΔH_(V)is not available, several methods have been developed which use thesummation of atomic and group contributions to ΔH_(V):ΔH_(V)=Σ_(i)Δh_(i),

where Δh_(i) is the contribution of the ith atom or group to the molarheat of vaporization. One convenient method has been proposed by R. F.Fedors, Polymer Engineering and Science, Vol. 14, p. 147 (1974). In thismethod ΔE_(V) and V are be obtained by simply assuming that

ΔE_(V)=Σ_(i)Δe_(i) and V=Σ_(i)v_(i) where ΔE_(i) and v_(i) are theadditive atomic and group contributions for the energy of vaporizationand molar volume, respectively.

Yet another method of calculating the solubility parameter of a materialis described by Small, J. Applied Chem. Vol. 3, p. 71 (1953).

Solubility parameters of some exemplary adhesive polymers are set forthin the '783 patent.

The transdermal permeation rate of the parent drug/prodrug combinationis controlled by varying the polymer components of the polymer adhesivecarrier so as to alter the difference in the solubility parameter of themultiple polymer adhesive carrier relative to that of the parentdrug/prodrug combination.

The transdermal permeation rate can also be controlled by varying therelative proportions of the polymers comprising the polymer adhesivecarrier.

The polymer adhesive carrier is preferably formulated so that it is apressure-sensitive adhesive at room temperature and has other desirablecharacteristics for adhesives used in the transdermal drug delivery art;such characteristics include good adherence to skin, ability to bepeeled or otherwise removed without substantial trauma to the skin,retention of tack with aging, etc. In general, the multiple polymeradhesive carrier should have a glass transition temperature (Tg),measured using a differential scanning calorimeter, of between about−70° C. and 0° C.

Selection of the particular polymer composition is governed in largepart by the parent drug/prodrug to be incorporated in the device, aswell as the desired rate of delivery of the parent drug/prodrug. Thoseskilled in the art can readily determine the rate of delivery of drugsfrom the polymer transdermal adhesive carrier in order to selectsuitable combinations of polymers and drug for a particular application.Various techniques can be used to determine the rate of delivery of thedrug from the polymer. Illustratively, the rate of delivery can bedetermined by measuring the transfer of drug from one chamber to anotherthrough cadaver skin over time, and calculating, from the obtained data,the drug delivery or flux rate. Specific polymers, such as preferredacrylic-based and silicone-based polymers, are described below.

The other method for controlling the blood plasma profile of subject isin the selection of the prodrug, such as based on its molecular weightor polarity. By increasing the molecular weight of the prodrug, the timeto the onset of permeation of effective amounts of the prodrug willincrease relatives to the parent drug. One example of this effect is inthe use of norethindrone and norethindrone acetate. The permeation rateof norethindrone rapidly peaks after application, whereas norethindroneacetate having a higher molecular weight reaches a maximum after thenorethindrone permeation rate begins to decline. See, e.g., FIG. 2.

In a related fashion, as the molecular weight of the prodrug increases,the permeation rate of the prodrug will be slower than the parent drug.Consequently, increasing the concentrations of higher molecular weightprodrugs can be used to offset decreasing permeation rates of parentdrugs where continued drug delivery over time is desired.

Of course, it should be understood that there is a certain degree ofinterrelationship between the two broad concepts described above. Forexample, molecular weight will affect both the amount of prodrug thatcan solubilized in the carrier as well as its transport through theskin.

Another parent drug/prodrug combination method to control the bloodprofile level is by the selection of a prodrug based on its differentpolarity. As explained in copending application Ser. No. 10/014,785, itis believed that the more lipophilic prodrug facilitates the entry ofthe prodrug into the stratum corneum of the intact skin of a subjectwhere it is ultimately hydrolyzed into the pharmacologically active andmore polar parent drug. The hydrolysis of the blocked functional groupin the prodrug to the functional groups in the parent drug, in turn,accelerates the diffusion of the drug through the skin and into theblood of the subject. That is, the more lipophilic prodrug is initiallydrawn into the lipophilic stratum corneum at a rate faster than thecorresponding parent drug. During transport through the skin, theprodrug is at least partially hydrolyzed back into the parent drug. Ashydrolysis takes place, the more polar parent drug is expelled from thelipophilic skin into the relatively polar blood stream. Thus, byselecting the prodrug based on its polarity, the permeation rate acrossthe skin can be controllably increased relative to the correspondingparent drug. Thus, by using a prodrug in addition to the parent drug,the composition will provide a faster permeation rate and onset.

Also, the onset and duration may be also controlled by the use ofprodrugs, due to the fact that systemic metabolism of the parent drugmay be reduced by the use of prodrugs. See generally, Bundgaard. Thatis, selection of appropriate prodrug allows even greater duration ofeffective therapy when in-vivo conversion rates to the active parentdrug entity are concerned. Initial dose can be introduced as the activeparent drug entity while concomitant administration of a long-actingprodrug occurs. The long-acting prodrug will be metabolized, e.g., overthe course of days to weeks to maintain therapeutic levels of activeparent drug. Examples of commercially available long-acting esters arehaloperidol decanoate (Haldol®) and testosterone enanthate(Delatestryl®). Parenteral administration of these molecules result intherapeutic levels of parent drug being sustained for 2-4 weeks. Asimilar long acting effect would be expected in transdermal drugdelivery.

The inventor has also found that the inventive combination of a parentdrug and prodrug can effect the melting point and hence thecrystallization of the parent drug/prodrug combination in the carrier.The quantity of drug loading possible, without crystallization, intransdermal platforms is dictated by many factors. Among these are drugfunctionality (acidic, basic), drug polarity or lack of polarity,solvents, matrix polymers and other excipient selections. Typically, thesolvents, polymers and excipients are used in a plethora of combinationsto optimize transdermal drug delivery for a given drug.

The melting point of a pure drug is constant at STP and must beconsistent lot to lot to be pharmaceutically acceptable as a rawmaterial. The inventor has found a pharmaceutically acceptable way ofreducing the purity (and thereby the melting point) of a given drugwhile still maintaining a pharmacologically equivalent effect, byutilizing the parent drug/prodrug combination. The two compoundsinteract to produce a mixture that exhibits a lower initial meltingpoint than either individual compound. This lower melting point parentdrug/prodrug combination results in substantial permeation rateenhancement when properly incorporated into transdermal platforms. Thisenhancement is due primarily to increased non-crystallized drug loadingpossible with these blends. Observations show (a) increased drug fluxwith the parent drug/prodrug mixtures flux over each individually (FIG.7) and (b) increased permeation of parent drug is achieved by increasingprodrug loading (FIGS. 5 and 6).

Use of a prodrug for enhancement of drug permeation is preferred toincorporating small molecule enhancers such as ethanol, polyhydricalcohols or terpenes because such prodrugs also contribute to achievingdelivery of a therapeutically effective dose. Moreover, use of prodrugsrather than small molecule enhancers can reduce or eliminate irritation,stability and processing issues associated with such enhancers whenmaking a transdermal system.

The melting point depression for various combinations of norethindroneand norethindrone acetate and estradiol and an estradiol prodrug areshown in Tables I and II. The indicated amounts of parent drug andprodrug were mixed by sieving the crystal powder drugs through a 250micron screen. A sample of each mixture was placed in a capillary tubeand melting point measurements were performed according to USP ReferenceStandards using a Haake melting point apparatus. All ratios demonstratedepressed melting points when compared to samples of the individualcompounds although optimal depression of melt point ranges is observedwhen the amount of prodrug exceeds the parent drug.

TABLE I Melting Point Ranges Norethindrone Initial Melting Final MeltingNorethindrone Acetate Point ° C. Point ° C. 40 mg 40 mg 146 183 20 mg 40mg 147 174 20 mg 60 mg 146 171 20 mg 80 mg 146 155 10 mg 90 mg 147 15440 mg 20 mg 147 191 80 mg 20 mg 148 197 90 mg 10 mg 152 202 50 mg  0 mg206 209  0 mg 50 mg 163 166

Similar testing was performed with estradiol and some of itscorresponding prodrug at a 1:1 ratio. The results, shown in Table II,also demonstrate a depressed melting point range. Utilizing a lowmelting point estradiol prodrug appears to be best at loweringestradiol's melting point.

TABLE II Compound Melting Point Range ° C. Estradiol 177 Estradiol17-enanthate 94-95 Estradiol 17-acetate 220-222 Estradiol: estradiol17-enanthate  88-129 Estradiol: estradiol 17-acetate 162-200

It appears that a melting point depression is achieved by combining aparent drug and a prodrug, and this phenomenon likely accounts forcrystal inhibition in such transdermal combination platforms. Examiningmelt point interactions of two or more combined drug entities providesan improved method of predicting and achieving drug crystal inhibition.Melt point interactions are also a simpler methodology than solubilityparameter crystallization observations since solubility parameterdetermining factors are far more numerous and often somewhat moredifficult to define. Accordingly, melt point depression measurementswill provide another tool by which desirable drug combinations can bedetermined, and subsequently tested for skin permeation performance insuitable matrix platforms.

Prodrugs that would be most useful are those that lower the parentdrug/prodrug combination's melting point the greatest. Parentdrug/prodrug combinations that exhibited higher melting points (than thelowest melting point individually) would be particularly useful incontrolling permeation rates which were otherwise too high or fast, orexhibited drug depletion prior to the end of the desired time period.

This becomes particularly important in formulating the next generationof transdermal drug delivery systems (particularly for hormonereplacement therapy) that will be required to deliver a therapeuticallyeffective amount of a drug over the course of up to one week or more. Toachieve an extended delivery, increasing drug concentration is typicallyrequired but in turn increases problems of crystallization. Determiningthe melting point of parent drug/prodrug combinations will provide amethod and a means of optimizing and controlling permeation rates.

Results of melting point effects on crystalline drug combination (i.e.,parent and prodrugs) suggest that preferred embodiments of thisinvention will utilize prodrugs with lower melting points than theparent drug.

Particularly useful drug combinations include steroids and theircorresponding prodrugs, such as those steroids described herein. It hasbeen found that estradiol enanthate and estradiol propionate arepreferred in combination with estradiol versus estradiol acetate. Withtestosterone, testosterone enanthate is preferred over testosteroneproprionate. Other useful drugs include ACE inhibitors and theirprodrugs, such as ramipril and its prodrugs, particularly ramiprilmethyl ester and ramipril ethyl ester. For the general invention, theweight ratio of the parent drug:prodrug is preferably 10:1 to 1:10. Amore preferred ratio is 6:1 to 1:6 and more preferably 1:3 to 3:1.

In a particularly preferred aspect of the invention, the parent drug isramipril and the prodrug is ramipril methyl ester and/or ramipril ethylester. Consistent with the present invention, applicants have found thatthe use of ramipril together with one of its prodrugs, in this case themethyl or ethyl ester, has been found to provide a modified flux (inthis case an increased flux) over the parent drug or prodrug alone. Theuse of the methyl ester with the parent drug ramipril is preferred sinceit provides a greater flux than the ethyl ester. The preferred weightratio for ramipril:ramipril methyl ester is generally 2:1 to 1:9. Thepreferred weight ratio for ramipril:ramipril ethyl ester is generally1:1 to 1:5, more preferably 1.1:1 to 1.1:5.

In a particularly preferred aspect of the invention, the parent drug isa steroid and the prodrug is a corresponding steroid derivative. Usefulfor this aspect of the invention are steroids having a free hydroxygroup at a position on the steroid ring, such as the 17-position, the3-position, or at the 11-position on the fused ring. Particularlypreferred are hormones such as estrogens, progestins, and androgens. Thecorresponding steroid prodrug (in this embodiment called steroidderivative) is defined as a corresponding structure to the steroid wherethe free hydroxy at the 3, 11 or 17 position has been reacted with analcohol reactive moiety. Particularly preferred are steroid derivativesreacted at the 17 position. Regardless of whether the steroid or thecorresponding steroid derivative is incorporated in the carriercomposition as the dominant drug, each provides a source of steroid inthe bloodstream to achieve the intended physiological effect which, inthe case of the corresponding steroid derivative, occurs throughmetabolic conversion of the derivative.

A steroid ester is the corresponding structure to the steroid where thefree hydroxy group on the ring has been esterified. Examples of asteroid and its corresponding ester include estradiol and estradiolbenzoate, estradiol 17-beta cypionate, estradiol 17 propionate,estradiol hemisuccinate (eutocol), estradiol enanthate, estradiolundecylate estradiol acetate, and estradiol propionate, etc. Anotherexample is testosterone and its corresponding ester of testosterone suchas 17 beta-cypionate, testosterone enanthate, testosterone nicotinate,testosterone phenylacetate, testosterone propionate, etc. Also includedare non-esters that have groups on the 17 position such as testosterone17-chloral hemiacetal, or ethers that have groups on the 3-position suchas estradiol 3-methyl ether.

Other steroids that can be used include progestins such asallylestrenol, anagestone, desogestrel, dimethisterone, dydrogesterone,ethisterone, ethynodiol, gestodene, haloprogesterone,17-hydroxy-16-methylene-progesterone, 17.alpha.-hydroxyprogesterone,lynestrenol, medroxyprogesterone, melengestrol, norethindrone,norethynodrel, norgesterone, norgestimate, norgestrel, norgestrienone,norvinisterone, pentagestrone, and trimigestone.

Anabolic steroids can include androisoxazole, androstenediol, bolandiol,bolasterone, clostebol, ethylestrenol. formyldienolone,4-hydroxy-19-nortestosterone, methandriol, methenolone,methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone andtrenbolone. Androgenic steroids can include boldenone, fluoxymesterone,mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone,17.alpha.-methyltestosterone 3-cyclopentyl enol ether, norethandrolone,normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone,stanlolone, stanozolol, testosterone, testosterone 17-chloral hemiacetaland tiomesterone.

Estrogens can include conjugated estrogenic hormones, equilenin,equilin, estradiol, estradiol benzoate, estradiol 17.beta.-cypionate,estriol, estrone, ethinyl estradiol and mixtures thereof.

Further steroids can include glucocorticoids such as21-Acetoxyprefnenolone, Aalclometasone, Algestone, Amicinonide,Beclomethasone, Betamethasone, Budesonide, Chloroprednisone, Clobetasol,Blovetasone, Clocortolone, Cloprednol, Corticosterone, Cortisone,Cortivazol, Deflazacort, Desonide, Desoximetasone, Dexamethasone,Diflorasone, Diflucortolone, Difluprednate, Enoxolone, Fluazacort,Flucloronide, Flumehtasone, Flunisolide, Fluocinolone Acetonide,Fluocinonide, Fluocortin Butyl, Fluocortolone, Fluorometholone,Fluperolone, Fluprednidene, Fluprednisolone, Flurandrenolide,Formocortal, Halcinonide, Halometasone, Halopredone, Hydrocortamate,Hydrocortisone, Mazipredone, Medrysone, Meprednisone,Methyolprednisolone, Mometasone Furoate, Paramethasone, Prednicarbate,Prednisolone, Prednisone, Prednival, Prednylidene, Tixocortal, andTriamcinolone,

Also included are mineralocorticoids such as Aldosterone,Deoxycorticosterone and Fludrocortisone.

In typical known devices the corresponding steroid derivative isadministered in view of crystallizations problems that occur with theuse of the non-derivative steroid. The present inventors have discoveredthat when the steroid is administered together with its correspondingsteroid derivative, a synergism in flux is observed as well as areduction in crystallization. That is, the flux from the combination ofsteroid and steroid derivative is greater than the flux of an equalamount of steroid or steroid derivative alone. For example, in a systemthat contains estradiol and norethindrone acetate, the addition ofnorethindrone and a reduction in the amount of norethindrone acetatesuch that the combined amount equals the original amount ofnorethindrone acetate results in increased delivery ofnorethindrone/norethindrone acetate.

Another unexpected advantage of the present invention is that the totalamount of steroid/corresponding steroid derivative delivered from thesystem is significantly greater than the amount drug from a compositioncontaining the steroid or corresponding steroid derivative alone. Forexample, applicants have found that for compositions containing bothnorethindrone acetate and norethindrone, the total amount of steroiddelivered from the system was 65% greater than a system containing acomparable amount of norethindrone acetate alone.

In order to achieve this synergistic effect, the weight ratio ofsteroid/corresponding steroid derivative is important. The ratio ispreferably in the range of 10:1 to 1:10 steroid:corresponding steroidderivative. A more preferred ratio is in the range of 6:1 to 1:6steroid:corresponding steroid derivative. The ratios providing thegreatest synergism depend on the pharmaceutically active agents in thesystem. For example, for the administration of the corresponding steroidand steroid derivative alone, a greater amount of steroid relative tocorresponding steroid derivative produces the greatest synergy. In thisembodiment, a preferred ratio is 1:1 to 3:1, more preferably 3:2 to 5:2,even more preferably about 2:1. However, when an additional steroid ispresent (such as estradiol) the opposite ratio gives the greatestsynergy. In this embodiment, a preferred ratio is 1:1 to 1:3, morepreferably 2:3 to 2:5, even more preferably 1:2 steroid:correspondingsteroid derivative. Any ratio that provides a synergistic flux is withinthe scope of the present invention.

Moreover, it further has been found that combinations of steroidderivatives also result in inhibiting crystallization of the drugspecies in the transdermal carrier compositions, with certainderivatives again working better than others. As shown in Table III, theaddition of estradiol methyl ether to estradiol acetate in a transdermalcarrier composition significantly improves crystal inhibition, whereasthe combination of estradiol acetate and estradiol propionate shows noimprovement, at the concentrations tested. The examples were observedthrough a microscope for crystal formation after two weeks maintained at25° C. and a relative humidity of 65% to 70%, using a viewing field of38.5 mm².

TABLE III EXAM- EXAM- EXAM- EXAM- EXAM- PLE PLE PLE PLE PLE % INGREDIENTA B C D E Estradiol acetate 3 — — 3 3 Estradiol propionate — 3 — 3 —Estradiol methyl — — 3 — 3 ether Acrylic Adhesive 5 5 5 5 5 (GMS 788)Oleyl Alcohol 6 6 6 6 6 Dipropylene Glycol 9 9 9 9 9 Silicone Adhesive75 75 75 72 72 (BIO-PSA 7-4603) Polyvinyl- 2 2 2 2 2 pyrrolidone(KOLLIDON-30) CRYSTAL ≧100 Long None Branched ≦2 FORMATION branchedcrystals crystals throughout throughout

Determining which steroid derivatives work better than others incombination with steroids or other steroid derivatives can be determinedthrough routine experimentation using the present specification as aguide.

The following description is described with respect to parentdrugs/prodrugs generally, but applies equally to the preferredembodiment of steroid/steroid derivatives described above.

The combined amount of parent drug/prodrug present in the compositioncan vary broadly and depends on many factors such as the carrier, thelength of administration, desired therapeutic effect, etc. The minimumamount of parent drug/prodrug in the system is selected based on theamount of parent drug/prodrug which passes through the skin in the timespan for which the composition is to provide therapy. Normally, theamount of parent drug/prodrug in the composition can vary from about0.1% to about 50% by weight, and preferably, for the lowersteroid/corresponding steroid derivative doses permitted by thisinvention, from about 0.3% to about 20%. Other possible ranges caninclude 0.1% to 10%, or 0.1% to 6% by weight.

The drug is present in a carrier. “Carrier” or “vehicle” as used hereinrefers to carrier materials suitable for transdermal drugadministration, and include any such materials known in the art, e.g.,any liquid, gel, solvent, liquid diluent, solubilizer, polymer or thelike, which is nontoxic and which does not significantly interact withother components of the composition or the skin in a deleterious manner.The carrier is present in an amount sufficient to achieve its functionof carrying the parent drug/prodrug. Preferably, the carrier is presentin an amount ranging from 2 to 99 wt %, more preferably 30 to 90 wt %,even more preferably 40 to 80 wt %. The carrier is preferablysubstantially free of water and more preferably contains no water.

Particularly preferred carriers are flexible, finite compositions. Thephrase “flexible, finite system” is intended to mean a solid formcapable of conforming to the surface with which it comes into contact,and which is capable of maintaining the contact in such solid form so asto facilitate topical application without adverse physiologicalresponse, and without being appreciably decomposed by aqueous contactduring administration to a patient. Particularly preferred flexible,finite systems are polymer carriers such as pressure-sensitive adhesivematrix type in which the parent drug/prodrug is dispersed directly inthe pressure-sensitive adhesive or reservoir type carriers.

Illustrative examples of suitable adhesives as matrix type flexible,finite delivery systems include those described in U.S. Pat. Nos.5,474,783, and 5,656,386 both assigned to Noven Pharmaceuticals, Inc.,Miami, Fla. (incorporated herein by reference in their entireties).Other flexible, finite systems known in the art include films, plasters,dressings, and bandages, as well as multilayer delivery systems in whichthe parent drug/prodrug is solubilized or contained in one or moreseparate layers and reservoir-type delivery systems in which the parentdrug/prodrug is solubilized or contained in a reservoir or depotseparate from the adhesive which attaches directly to the skin ormucosa.

As noted above, particularly preferred carriers are pressure-sensitiveadhesive flexible, finite carriers. These can include any viscoelasticmaterial which adheres instantaneously to most substrates with theapplication of very slight pressure and remains permanently tacky. Apolymer is a pressure-sensitive adhesive within the meaning of the termas used herein if it has the properties of a pressure-sensitive adhesiveper se or functions as a pressure-sensitive adhesive by admixture withtackifiers, plasticizers or other additives. The term pressure-sensitiveadhesive also includes mixtures of different polymers and mixtures ofpolymers, such as polyisobutylenes (PIB), of different molecularweights, wherein each resultant mixture is pressure-sensitive. Otheruseful rubber based pressure-sensitive adhesives include hydrocarbonpolymers such as natural and synthetic polyisoprene, polybutylene andpolyisobutylene, styrene/butadiene polymers styrene-isoprene-styreneblock copolymers, hydrocarbon polymers such as butyl rubber,halogen-containing polymers such as polyacrylic-nitrile,polytetrafluoroethylene, polyvinylchloride, polyvinylidene chloride, andpolychlorodiene, and other copolymers thereof.

Other useful pressure-sensitive adhesives (“PSA”) can includeacrylic-based pressure-sensitive adhesives and silicone-basedpressure-sensitive adhesives as described in U.S. Pat. Nos. 5,474,783,and 5,656,386. Suitable commercially available acrylic-based polymerscan include adhesives are commercially available and include thepolyacrylate adhesives sold under the trademarks Duro-Tak by NationalStarch and Chemical Corporation, Bridgewater, N.J., such as Duro-Tak87-2194, Duro-Tak 87-2196, Duro-Tak 87-1197, 87-4194, 87-2510, 87-2097and 87-2852. Other suitable acrylic-based adhesives are those sold underthe trademarks Gelva-Multipolymer Solution (GMS) (Monsanto; St. Louis,Mo.), such as GMS 737, 788, 1151, 3087 and 7882.

Suitable silicone-based pressure-sensitive adhesives can include thosedescribed in Sobieski, et al., “Silicone Pressure Sensitive Adhesives,”Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 508-517(D. Satas, ed.), Van Nostrand Reinhold, New York (1989), incorporated byreference in its entirety. Other useful silicone-based pressuresensitive adhesives are described in the following U.S. Pat. Nos.4,591,622; 4,584,355; 4,585,836; and 4,655,767. Suitable silicone-basedpressure-sensitive adhesives are commercially available and include thesilicone adhesives sold under the trademarks BIO-PSA 7-4503, BIO-PSA7-4603, BIO-PSA 7-4301, 7-4202, 7-4102, 7-4106, and BIO-PSA 7-4303 byDow Corning Corporation, Medical Products, Midland, Mich.

The amount of the polymer carrier can range from 2 to 99 wt %,preferably, 30 to 90 wt %, even more preferably 40 to 80 wt %.

The pressure-sensitive adhesives can be blended to modulate thesolubility of the drug in the carrier system such as described in the'783 patent. In a particularly preferred embodiment of the invention,the multiple polymer adhesive system comprises a pressure-sensitiveadhesive blend of an acrylic-based polymer, a silicone-based polymer,and a soluble PVP (described below). The acrylic-based polymer andsilicone-based polymer are preferably in a ratio by weight,respectively, from about 2:98 to about 96:4, more preferably from about2:98 to about 90:10, and even more preferably about 2:98 to about 86:14.The amount of acrylic-based (also referred to broadly as a polyacrylate)polymer and silicone-based polymer (also referred to broadly as apolysiloxane) is adjusted so as to modify the saturation concentrationof the parent drug/prodrug in the ternary multiple polymer adhesivesystem in order to affect the rate of delivery of the parentdrug/prodrug from the system and through the skin. Other useful rangesinclude about 5-85% by weight of the acrylate-based polymer, 10-90% byweight of polyisobutylene and 5-95% by weight of silicone-based polymer.

The transdermal drug delivery system can also contain agents known toaccelerate the delivery of the parent drug/prodrug through the skin.These agents have been referred to as skin-penetration enhancers,accelerants, adjuvants, and sorption promoters, and are collectivelyreferred to herein as “enhancers” and are described in U.S. Pat. No.6,221,383. They can include polyhydric alcohols such as dipropyleneglycol, propylene glycol, and polyethylene glycol which enhance parentdrug/prodrug solubility; oils such as olive oil, squalene, and lanolin;fatty ethers such as cetyl ether and oleyl ether; fatty acid esters suchas isopropyl myristate which enhance parent drug/prodrug diffusibility;urea and urea derivatives such as allantoin which affect the ability ofkeratin to retain moisture; polar solvents such asdimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamide,dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide,decylmethylsulfoxide, and dimethylformamide which affect keratinpermeability; salicylic acid which softens the keratin; amino acidswhich are penetration assistants; benzyl nicotinate which is a hairfollicle opener; and higher molecular weight aliphatic surfactants suchas lauryl sulfate salts which change the surface state of the skin anddrugs administered. Other agents include oleic and linoleic acids,ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol,tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropylpalmitate. Particularly preferred are combinations of polyhydricalcohols such as glycerine, dipropylene glycol, butylene glycol,propylene glycol and one or more of oleyl alcohol and oleic acid.

In some embodiments, the invention can also include a plasticizer ortackifying agent is incorporated into the formulation to improve theadhesive characteristics of the pressure-sensitive adhesive composition.Such plasticizers or tackifying agents include: (1) aliphatichydrocarbons; (2) mixed aliphatic and aromatic hydrocarbons; (3)aromatic hydrocarbons; (4) substituted aromatic hydrocarbons; (5)hydrogenated esters; (6) polyterpenes; and (7) hydrogenated wood rosins.

The tackifying agent employed is preferably compatible with the blend ofpolymers. In preferred embodiments, the tackifying agent is siliconefluid (e.g., 360 Medical Fluid, available from Dow Corning Corporation,Midland, Mich.) or mineral oil. Silicone fluid is useful for blendscomprising polysiloxane as a major component. In other embodiments,where a synthetic rubber, for example, is a major component, mineral oilis a preferred tackifying agent.

For parent drug/prodrug molecules which are not readily soluble in thepolymer system, a co-solvent for the parent drug/prodrug and polymer canbe added. Co-solvents, such as lecithin, retinal derivatives,tocopherol, dipropylene glycol, triacetin, propylene glycol, saturatedand unsaturated fatty acids, mineral oil, silicone fluid, alcohols,butyl benzyl phthalate, and the like are useful in the practice of theinstant invention depending on the solubility of the parent drug/prodrugin the multiple polymer adhesive system.

In addition to the use of the parent drug/prodrug combinations toinhibit crystallization, other crystallization inhibiting agents can beused. One known agent is polyvinylpyrrolidone (PVP), preferably solublePVP as described in detail in U.S. Pat. No. 6,221,383. The term“polyvinylpyrrolidone,” or “PVP” refers to a polymer, either ahomopolymer or copolymer, containing N-vinylpyrrolidone as the monomericunit. Typical PVP polymers are homopolymeric PVPs and the copolymervinyl acetate vinylpyrrolidone. The homopolymeric PVPs are known to thepharmaceutical industry under a variety of designations includingPovidone, Polyvidone, Polyvidonum, Polyvidonum soluble, andPoly(1-vinyl-2-pyrrolidone). The copolymer vinyl acetatevinylpyrrolidone is known to the pharmaceutical industry as Copolyvidon,Copolyvidone, and Copolyvidonum. The term “soluble” when used withreference to PVP means that the polymer is soluble in water andgenerally is not substantially cross-linked, and has a molecular weightof less than about 2,000,000. The PVP usable with the present invention,preferably has a molecular weight of about 2,000 to 1,100,000, morepreferably 5,000 to 100,000, and most preferably 7,000 to 54,000.

The amount and type of PVP required in the foregoing preferredembodiment will depend on the quantity and type of parent drug/prodrugpresent in the adhesive, as well as the type of adhesive, but can bereadily determined through routine experimentation. Typically, the PVPis present in an amount from about 1% to about 20% by weight, preferablyfrom about 3% to about 15% by weight. However, the amount of PVP can behigher than 20% for example, up to 40%, depending on the particularparent drug/prodrug used and on the desired properties of the blend. Onecommercially useful PVP is sold under “Kollidon,” such as “Kollidon 10,”“Kollidon 17 PF,” “Kollidon 25,” “Kollidon 90,” “Kollidon 30,” and “VA64” a trademark of BASF AG, Ludwigshafen, Germany. Another useful PVP issold under Kollidon CL-M also a trademark of BASF AG.

The compositions of this invention may further be provided with variousthickeners, fillers and other additives known for use with transdermaldrug delivery systems. Where the composition tends to absorb water, forexample, when lecithin is used as a co-solvent, hydrophilic substancesare especially useful. One type of hydrophilic substance which has beensuccessfully employed is clay. The addition of clay has been found toimprove adhesiveness in transdermal formulations without reducing therate of parent drug/prodrug delivery. Suitable clays include aluminumsilicate clay, kaolinite, montmorillonite, atapulgite, illite,bentonite, halloysite and the like.

A device, or individual dosage unit, of the present invention can beproduced in any manner known to those of skill in the art. After thedermal composition is formed, it may be brought into contact with thebacking layer in any manner known to those of skill in the art. Suchtechniques include calender coating, hot melt coating, solution coating,etc. Of course, backing materials are well known in the art and cancomprise plastic films of polyethylene, vinyl acetate resins,ethylene/vinyl acetate copolymers, polyvinyl chloride, polyurethane, andthe like, metal foils, non-woven fabric, cloth and commerciallyavailable laminates. The backing material generally has a thickness inthe range of 2 to 1000 micrometers and the dermal composition isgenerally disposed on backing material in a thickness ranging from about12 to 250 micrometers thick.

Suitable release liners are also well known in the art and include thecommercially available products of Dow Corning Corporation designatedBio-Release7. liner and Syl-off7 7610 liner. For preferred embodimentsin which a polysiloxane is part of the multiple polymeric adhesivecarrier, the release liner must be compatible with the siliconeadhesive. An example of a suitable commercially available liner is 3M's1022 Scotch Pak.7 The configuration of the transdermal delivery systemof the present invention can be in any shape or size as is necessary ordesirable. Illustratively, a single dosage unit may have a surface areain the range of 1 to 200 cm². Preferred sizes are from 5 to 60 cm^(z).

In a preferred method aspect of the invention where the carrier is aflexible, finite polymer, one or more polymers are blended, optionallywith PVP to result in a pressure-sensitive adhesive composition, ortransdermal drug delivery system adhesive system (with incorporatedparent drug:prodrug), which controls delivery of an incorporated parentdrug:prodrug and through the epidermis. In a preferred embodiment of theinvention, a transdermal drug delivery system is prepared by mixing asoluble PVP, polyacrylate, polysiloxane, parent drug/prodrug, optionalenhancer(s), co-solvent(s), and tackifying agents, if needed, in anappropriate volatile solvent(s), then casting the mixture and removingthe solvent(s) by evaporation to form a film. Suitable volatile solventsinclude, but are not limited to, alcohols such as isopropanol andethanol; aromatics such as xylenes and toluene; aliphatics such ashexane, cyclohexane, and heptane; and alkanoic acid esters such as ethylacetate and butyl acetate.

An exemplary general method for the preparation of an embodiment is asfollows:

1. Appropriate amounts of solvent(s), optional enhancer(s), optional PVPand organic solvent(s) (for example toluene) are combined and thoroughlymixed together in a vessel.

2. The parent drug:prodrug is then added to the mixture and agitation iscarried out until the parent drug/prodrug is uniformly mixed in.

3. Appropriate amounts of polymer are then added to the parentdrug/prodrug mixture, and thoroughly mixed.

4. The formulation is then transferred to a coating operation where itis coated onto a protective release liner at a controlled specifiedthickness. The coated product is then passed through an oven in order todrive off all volatile processing solvents.

5. The dried product on the release liner is then joined to the backingmaterial and wound into rolls for storage.

6. Appropriate size and shape “systems” are die-cut from the rollmaterial and then pouched.

The order of steps, the amount of the ingredients, and the amount andtime of agitation or mixing may be importance process variables whichwill depend on the specific polymers, parent drug/prodrug, cosolvents,and enhancers used in the formulation. These factors can be adjusted bythose skilled in the art, while keeping in mind the object of providinga uniform product. It is believed that a number of other methods,including changing some of the order of steps, can be carried out andwill give desirable results. In addition to having various shapes, thedosage units produces may come in various sizes. A surface area in therange of 1 to 200 square centimeters is contemplated, and the presentlypreferred sizes are: 5, 10, 15, 20, 30, 40, and 60 are centimeters.

EXAMPLES

The following specific examples are included as illustrative oftransdermal delivery systems and compositions within the contemplationof the invention. These examples are in no way intended to be limitingof the scope of the invention. The weights percentages in the examplesare based on dry weight of the system, unless other noted. In thefigures, “NET” stands for norethindrone, and “NETA” stands fornorethindrone acetate.

The following commercially available adhesives were used in theexamples: “Duro-Tak 87-2287” is a trademark of NATIONAL STARCH ANDCHEMICAL CORPORATION, Bridgewater, N.J. for polyacrylate adhesives inorganic solutions.

“Bio-PSA 7-4603” is a trademark of DOW CORNING CORPORATION, MEDICALPRODUCTS, Midland, Mich. for polysiloxane adhesives in organicsolutions.

“Gelva-Multipolymer Solution (GMS) 737 and 788” are trademarks of theMonsanto Company, Saint Louis, Mo. for polyacrylate adhesives in organicsolution.

“KOLLIDON 30 and VA 64” are trademarks of BASF Aktiengesellschaft,Ludwigschaften, Germany for polyvinylpyrrolidone polymers and the vinylacetate/vinylpyrrolidone copolymer.

Example 1 and Comparative Example 1

A transdermal delivery composition was prepared with the followingingredients:

Norethindrone 1.2% Estradiol 0.9 Norethindrone Acetate 2.5 PVP/VACopolymer (VA64) 15.0 Acrylic PSA (GMS737) 5.0 Oleic Acid 3.0Dipropylene Glycol 9.0 Silicone PSA (7-4603) 63.4

Flux of the steroids through the cadaver skin in vitro from theformulation of Example 1 is shown in FIG. 1 as triangles (Δ and ▴). Alsoshown as a comparative example (“CE”) is the flux for the commerciallyavailable CombiPatch

product that contains only estradiol and norethindrone acetate, whichare shown as circles (O or ●). As FIG. 1 indicates, the flux for thecombined norethindrone/norethindrone acetate of Example 1 wassignificantly higher than norethindrone acetate alone of the CombiPatch

product, while the flux of estradiol was unaffected. The flux ofestradiol was approximately the same.

Example 2 and Comparative Examples (CE) 2

Transdermal steroid/corresponding steroid derivative deliverycompositions were prepared with the following ingredients:

Formulation CE 2-1 CE 2-2 Ex. 2 Norethindrone 1.2% 0% 1.2% Estradiol 0.90.9 0.9 Norethindrone Acetate 0 2.5 2.5 PVP/VA Copolymer (VA64) 15.015.0 15.0 Acrylic PSA (GMS737) 5.0 5.0 5.0 Oleic Acid 3.0 3.0 3.0Dipropylene Glycol 9.0 9.0 9.0 Silicone PSA (7-4603) 65.9 64.6 63.4

Flux of the combined norethindrone/norethindrone acetate through thecadaver skin in vitro from the formulation of Example 2 is shown in FIG.2 as circles (●). Also shown are comparative examples that containedonly norethindrone and norethindrone acetate, which are shown as squares(▪) and triangles (▴), respectively. As FIG. 2 indicates, the flux forthe combined norethindrone/norethindrone acetate was significantlyhigher than either norethindrone or norethindrone acetate alone, inessentially in the same carrier composition.

Example 3 and Comparative Examples 3

A transdermal steroid/corresponding steroid derivative deliverycomposition was prepared with the following ingredients:

testosterone 6.0% testosterone acetate 3.0 PVP Kollidon 30 12.0 acrylicPSA (GMS788) 5.0 oleic Acid 3.0 dipropylene Glycol 9.0 silicone PSA(7-4603) 63.4

Flux of the combined testosterone/testosterone acetate through thecadaver skin in vitro from the formulation of Example 3 is shown in FIG.3 as squares (▪). Also shown are the separate flux of testosterone andtestosterone acetate from the formulation of Example 3, shown as circles(●) and dark triangles (▴), respectively. Also shown is the flux of acommercially available testosterone composition sold under the trademarkTestoderm7 sold by Alza, Inc., shown as open triangles (Δ). As FIG. 3indicates, the flux for the combined testosterone/testosterone acetateof Example 3 was significantly higher than the Testoderm7 composition.Also, the individual fluxes of the testosterone and testosterone acetateof Example 3 were each greater than the flux of Testoderm7 andaccordingly demonstrate that each drug entity is being delivered in anamount sufficient to provide a physiological effect.

Example 4 and Comparative Examples 4

Transdermal steroid/steroid derivative delivery compositions wereprepared with the following ingredients:

Ex 4-1 Ex. 4-2 Ex. 4-3 Ex. 4-4 Estradiol 4% 4% 4% 4% Estradiol Acetate2.5 — — Estradiol Enanthate — — 2.5 — Estradiol Propionate — — — 2.5Kollidon 30 3 3 3 3 Oleyl Alcohol 6 6 6 6 Dipropylene Glycol 9 9 9 9Duro-Tak 87-2287 7 7 7 7 Silicone PSA 7-4603 71 68.5 68.5 68.5

Examples 4-1 and 4-2 had crystals after 3 days. Examples 4-3 and 4-4 hadno crystals at 13 days. From these results the acetate ester ofestradiol is not as effective in inhibiting crystals, whereas, thepropionate and enanthanate are effective in inhibiting crystals.

Examples 5-9

Transdermal parent drug/prodrug delivery compositions were prepared withthe following ingredients:

Ingredients (w/w %) Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Polysiloxane PSA 52 4946 43 46 (BIO-PSA ® 7-4603) Polyvinylpyrrolidone 25 25 25 25 25(Kollidon ® 30) Oleic Acid 5 5 5 5 5 Dipropylene Glycol 15 15 15 15 15Norethindrone 3 3 3 3 0 Norethindrone Acetate 0 3 6 9 9

Examples 5 and 9 are comparative. The permeation rate ofnorethindrone/norethindrone acetate are shown in FIGS. 5-7. FIG. 5 showsthe average cumulative permeation for norethindrone for Examples 5-8.FIG. 6 shows average cumulative permeation for norethindrone acetate forExamples 6-9. FIG. 7 shows average cumulative permeation for combinednorethindrone and norethindrone acetate for Examples 5-9. All thefigures show increased permeation for parent drug/prodrug combinationscompared to the prodrug (in this case norethindrone acetate) or parentdrug.

The formulations of Examples 6-8 were also tested for crystal formation.Each blend was cast onto a polyester release liner (ScotchPak® 1022; 3M,Minneapolis, Mich.) with a 15 ml wet gap applicator. The cast downs wereair dried for five minutes at ambient temperature and humidity under ahood, and for an additional five minutes in a convection air oven at 92°C. to drive off any volatile solvents. Upon completion, the releaseliner coated with the dried drug mixture composition was laminated tothe polyester side of a polyester/ethylene vinyl acetate backingmaterial (ScotchPak® 9732; 3M, Minneapolis, Mich.). Individual units of10 cm² were die cut and placed under a microscope for visual inspectionat a magnification of 25×. The blends exhibited no crystal formationafter 60 days.

It appears that a melting point depression is achieved by combining aparent drug and a prodrug, and this phenomenon likely accounts forcrystal inhibition in such transdermal platforms.

Example 10

Prodrug effects on flux were also studied using an ace inhibitor drug,ramipril. Flux rates of two corresponding prodrugs—ramipril methyl esterand ramipril ethyl ester—were compared prior to combining with theparent drug. As shown in FIG. 9, without permeation enhancers, themethyl ester prodrug achieved a 73% higher flux than the ethyl esterprodrug in carrier formulations containing 20% drug, 20% polyacrylateadhesive (DURO-TAK® 87-90880, and 60% polysiloxane adhesive (BIO-PSA®7-4102). With the addition of 3% oleyl alcohol and 5% dipropylene glycolto the formulations (reducing the polysiloxane adhesive to 52%), theflux was nearly doubled. In either event, the use of an ester prodrug inplace of the parent drug can achieve, at the very least, over a 10 foldincrease in flux (see ramipril flux (▴) in FIG. 8—only 15% ramiprilcould be solubilized without forming crystals—versus ramipril ethylester flux without enhancers (Δ) in FIG. 9). Use of non-functional orhydroxy functional adhesives are also preferred.

However, when both ramipril and a corresponding prodrug are combined inthe formulations containing enhancers, an even higher flux can beobtained. As shown in FIG. 8, it was found that ramipril/prodrugcombinations significantly improved flux with the methyl ester prodrugcombination flux about doubling. In all formulations incorporatingramipril/methyl ester prodrug combinations, it was found that fluximproved over either drug alone with the addition of the prodrug.Optimal flux at 20% drug concentration was found when the ratio oframipril to the methyl ester prodrug was about 1:2.33, withoutsignificant improvement beyond a 1:3 ratio.

With ramipril/ethyl ester prodrug combinations, optimal flux at 20% drugconcentration was achieved at a ratio of about 1:3 ramipril/prodrug andhad about a 20% flux increase over ramipril ethyl ester alone. However,at about 1:1 ratio, it was found that flux actually decreased about 19%when compared to the flux of ramipril ethyl ester alone. Nonetheless,the ramipril/ethyl ester prodrug combination achieved a significant fluxincrease over ramipril alone. Accordingly, while it was found thatramipril/prodrug combinations provided improved flux over either drugentity alone, the ramipril methyl ester prodrug fluxed higher than theethyl ester derivative.

While a number of preferred embodiments of the present invention havebeen described, it should be understood that various changes,adaptations and modifications may be made therein without departing fromthe spirit of the invention and the scope of the appended claims.

1. A method for controlling the melting point of a drug used in a composition for transdermal delivery, comprising providing a pharmaceutically acceptable carrier comprising a pressure-sensitive adhesive and a combination of a drug and a corresponding pro-drug, wherein the drug/pro-drug combination begins to melt at a temperature that is lower than the melting points of each of the drug or pro-drug alone.
 2. The method of claim 1, wherein the weight/weight ratio of pro-drug:drug is
 1. 3. The method of claim 1, wherein the melting point of the pro-drug is lower than the melting point of the drug.
 4. The method of claim 1, wherein the drug comprises a steroid and the pro-drug comprises a corresponding steroid derivative.
 5. The method of claim 4, wherein the weight/weight ratio of steroid:corresponding steroid derivative is from 10:1 to 1:10.
 6. The method of claim 4, wherein the corresponding steroid derivative is the steroid where the free hydroxy group at the 3, 11 or 17 position has been reacted with an alcohol moiety.
 7. The method of claim 6, wherein the corresponding steroid derivative comprises the steroid where the free hydroxy group at the 17 position has been reacted with an alcohol moiety.
 8. The method of claim 1, wherein the drug comprises norethindrone and the prodrug comprises norethindrone acetate.
 9. The method of claim 8, wherein the weight/weight ratio of norethindrone acetate:norethindrone is 1:1.
 10. The method of claim 1, wherein the drug comprises estradiol and the prodrug comprises estradiol 17-enanthate.
 11. The method of claim 10, wherein the weight/weight ratio of estradiol 17-enanthate:estradiol is
 1. 12. The method of claim 1, wherein the drug comprises estradiol and the pro-drug comprises a pro-drug selected from the group consisting of estradiol benzoate, estradiol 17-β-cypionate, estradiol 17-propionate, estradiol hemisuccinate (eutocol), estradiol enanthate, estradiol undecylate, estradiol acetate, estradiol proprionate and estradiol 3-methyl ether.
 13. The method of claim 1, wherein the drug comprises testosterone and the pro-drug comprises a pro-drug selected from the group consisting of testosterone 17-β-cypionate, testosterone enanthate, testosterone nicotinate, testosterone phenylacetate, testosterone proprionate and testosterone 17-chloral hemiacetal.
 14. The method of claim 1, wherein the drug comprises ramipril and the pro-drug comprises a pro-drug selected from the group consisting of ramipril methyl ester and ramipril ethyl ester.
 15. The method of claim 1, wherein the drug comprises a progestin selected from the group consisting of allylestrenol, anagestone, desogestrel, dimethisterone, dydrogesterone, ethisterone, ethynodiol, gestodene, haloprogesterone, 17-hydroxy-16-methylene-progesterone, 17α-hydroxyprogesterone, lynoestrenol, medroxyprogesterone, melengestrol, norethindrone, norethynodrel, norgesterone, norgestimate, norgestrel, norgestrienone, norvinisterone, pentagestrone, and trimegestone.
 16. The method of claim 1, wherein the drug comprises an anabolic steroid selected from the group consisting of androisoxazole, androstenediol, bolandiol, bolasterone, clostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methandriol, methenolone, methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone and trenbolone.
 17. The method of claim 1, wherein the drug comprises an androgenic steroid selected from the group consisting of boldenone, fluoxymesterone, mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone, 17α-methyltestosterone 3-cyclopentyl enol ether, norethandrolone, normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone, stanlolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal and tiomesterone.
 18. The method of claim 1, wherein the drug comprises an estrogen selected from the group consisting of conjugated estrogenic hormones, equilenin, equilin, estradiol, estradiol benzoate, estradiol 17-β-cypionate, estriol, estrone, and ethinyl estradiol.
 19. The method of claim 1, wherein the drug comprises a glucocorticoid selected from the group consisting of 21-Acetoxyprefnenolone, Aalclometasone, Algestone, Amicinonide, Beclomethasone, Betamethasone, Budesonide, Chloroprednisone, Clobetasol, Blovetasone, Clocortolone, Cloprednol, Corticosterone, Cortisone, Cortivazol, Deflazacort, Desonide, Desoximetasone, Dexamethasone, Diflorasone, Diflucortolone, Difluprednate, Enoxolone, Fluazacort, Flucloronide, Flumehtasone, Flunisolide, Fluocinolone Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, Fluorometholone, Fluperolone, Fluprednidene, Fluprednisolone, Flurandrenolide, Formocortal, Halcinonide, Halometasone, Halopredone, Hydrocortamate, Hydrocortisone, Mazipredone, Medrysone, Meprednisone, Methyolprednisolone, Mometasone Furoate, Paramethasone, Prednicarbate, Prednisolone, Prednisone, Prednival, Prednylidene, Tixocortal, and Triamcinolone.
 20. The method of claim 1, wherein the drug comprises a mineralocorticoid selected from the group consisting of Aldosterone, Deoxycorticosterone and Fludrocortisone.
 21. The method of claim 1, wherein the composition exhibits increased drug permeation as compared to a corresponding composition that does not comprise the pro-drug.
 22. The method of claim 1, wherein the composition exhibits increased drug flux as compared to a corresponding composition that does not comprise the pro-drug.
 23. The method of claim 1, wherein the composition exhibits increased non-crystallized drug loading as compared to a corresponding composition that does not comprise the pro-drug. 